To link to the entire object, paste this link in email, IM or documentTo embed the entire object, paste this HTML in websiteTo link to this page, paste this link in email, IM or documentTo embed this page, paste this HTML in website

CANCER EPIGENETICS: LINKING BASIC MECHANISMS TO THERAPY
by
Han Han
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR PHARMACOLOGY AND TOXICOLOGY)
May 2013
Copyright 2013 Han Han

Due to the technology revolution in epigenetic profiling, the number of genes that contain epigenetic aberrations in disease is growing, emphasizing the critical role of epigenetics in disease states. The reversibility of epigenetic abnormalities upon pharmacological interventions has spurred interest in developing epigenetic therapy with the primary goal of restoring the expression of aberrantly silenced genes. The focus of this thesis was twofold: to elucidate the role of DNA methylation occurring at non-CpG island promoters and investigate mechanisms involved in therapeutic efficacy of a DNA methyltransferase inhibitor, 5-Aza-2'-deoxycytidine. ❧ In the field of epigenetics, the significance of CpG island methylation in both normal and disease states, especially in cancer, has been well elucidated. However, the importance of DNA methylation occurring at non-CpG island promoters and its potential role in tumorigenesis are still controversial. Using LAMB3 and RUNX3 as examples, I have shown that DNA methylation directly silences genes containing non-CpGI promoters and their epigenetic signatures are almost identical to CpG island promoters, suggesting aberrant methylation patterns of non-CpG island promoters may also contribute to tumorigenesis and should therefore be included in analyses of cancer epigenetics. ❧ The clinical efficacies of DNA methyltransferase inhibitors are irrefutable; however, mechanisms involved in therapeutic efficacy of these inhibitors are not completely understood. By investigating genome-wide changes in DNA methylation and gene expression at various time points after transient exposure to 5-Aza-CdR, I revealed that different genomic regions have different rate of remethylation upon drug withdrawal. In general, promoters remethylate much slower than gene bodies, resulting in sustained DNA demethylation and subsequent gene reactivation, which may potentially responsible for the less tumorigenic phenotype of cancer cells produced by transient exposure to 5-Aza-CdR. Elucidating the therapeutic efficacy of 5-Aza-CdR helps pave the way for developing combinatorial therapies to target multiple aberrant epigenetic modifiers. I also demonstrated the efficacy of combining 5-Aza-CdR with clorgyline, a lysine specific demethylase inhibitor, in enhancing the degree and prolonging the duration of gene reactivation. Taken together, this thesis presents the role of non-CpG island methylation and the therapeutic mechanism of 5-Aza-CdR, thus aiding in developing new epigenetic therapies, extending the application of and improving the efficacies of current therapies.

The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given.

CANCER EPIGENETICS: LINKING BASIC MECHANISMS TO THERAPY
by
Han Han
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR PHARMACOLOGY AND TOXICOLOGY)
May 2013
Copyright 2013 Han Han